This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin resistance, a state of impaired biological response to normal or elevated serum insulin concentration, is thought to be the pre-diabetic state which appears long before full blown diabetes is evident in obese subjects. Although the precise pathogenesis and the pathophysiological sequence resulting in insulin resistance are still largely unknown, alleviating insulin resistance is still one of the key avenues to treating type-2 diabetes. Recent evidence suggests that exceeding the capacity of the endoplasmic reticulum (ER stress) with concomitant activation of the unfolded protein response during obesity contributes to insulin resistance and the development of diabetes. Forkhead box class O transcription factor (FoxO3), peroxisome proliferator-activated receptor- coactivator (PGC-1-alpha), sirtuin deacetylase (SIRT1) and protein tyrosine phosphatase 1B (PTP1B) are some of the key downstream insulin signaling molecules that have also been shown to mediate insulin resistance either via changes in their protein levels and/or by posttranslational modifications such as phosphorylation and acetylation. The objective of this proposal is to investigate the molecular mechanisms by which ER-stress induces insulin resistance. The central hypothesis is that ER-stress induces insulin resistance via modulating insulin signaling molecules FoxO3, PGC1 alpha, SIRT1 and PTP1B. The outcome of these studies will help in delineating various pathways downstream of the insulin receptor and will address some of the gaps in the knowledge in our understanding of insulin signaling in conditions such as obesity and type-2 diabetes.